Key result
Cardiac-specific deletion of desmoglein 2 in mice led to early cardiomyocyte apoptosis (8% vs 0.47%) and an inflammatory macrophage response at 2 weeks, preceding severe cardiac fibrosis at 10 weeks.
Why the study?
Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, but how loss of desmoglein 2 in the young heart leads to disease development required examination.
Does loss of desmoglein 2 trigger early cardiac inflammation leading to fibrosis in a murine model of arrhythmogenic cardiomyopathy?
Does loss of desmoglein 2 trigger early cardiac inflammation leading to fibrosis in a murine model of arrhythmogenic cardiomyopathy?
Early cardiac inflammation, triggered by cardiomyocyte stress and apoptosis, precedes fibrosis in a murine model of arrhythmogenic cardiomyopathy, suggesting a potential early therapeutic target.
Early apoptosis and inflammation may initiate desmosomal cardiomyopathy; leaves open mechanistic targets for human ARVC trials.
The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic Cardiomyopathy (AC) is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 ( Dsg2 ) in the young murine heart leads to development of AC. Cardiomyocyte apoptosis was an early cellular phenotype and RNA-Seq analysis revealed early activation of inflammatory-associated pathways in Dsg2 null ( Dsg2 −/− ) hearts at postnatal day 14 (Two weeks) that were absent in the fibrotic heart of adult mice (Ten weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at different disease stages implicate inflammation related to loss of desmoglein 2 as a major mechanism for disease progression.
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NG et al. (2020) studied Arrhythmogenic Cardiomyopathy. Cardiac-specific deletion of desmoglein 2 (Dsg2-/-) vs. Wild type (Dsg2+/+) and heterozygous (Dsg2+/-) littermates was evaluated. Cardiac-specific deletion of desmoglein 2 in mice led to early cardiomyocyte apoptosis (8% vs 0.47%) and an inflammatory macrophage response at 2 weeks, preceding severe cardiac fibrosis at 10 weeks.
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